Project Summary Project Summary: Alcoholic liver disease (ALD) is a major cause of advanced liver disease worldwide. ALD consists of a spectrum of liver disorders, ranging from simple steatosis to more severe forms of liver injury, including alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. To reduce the incidence of ALD, abstinence from alcohol abuse is critical for prevention of the development of ALD. From the therapeutic standpoint, however, little progress has been made towards the treatment of ALD over the past 40 years. Carboxylesterase 1 (CES1) is a drug-metabolizing enzyme that is highly expressed in the liver and to a lesser extent in intestine, macrophages, heart, pancreas, kidney and adipose tissue. CES1 possesses both triglyceride (TG) and cholesterol ester hydrolase activity. We have previously shown that CES1 inhibits hepatic TG accumulation by regulating TG hydrolysis, FAO and lipogenesis. Gain of hepatic CES1 function is also shown to improve insulin sensitivity in diabetic or high fat diet-fed mice. Our preliminary data show that Ces1 -/- mice display aggravated alcohol-induced liver injury and inflammation while over-expression of CES1 inhibits inflammation and ethanol-induced TG accumulation. Based on these observations, we hypothesize that hepatic CES1 plays a protective role in the pathogenesis of ALD. To test this hypothesis, we will use liver-specific Ces1 knockout or transgenic mice to investigate the role of hepatic CES1 in ALD as well as the underlying mechanism. In addition, we will also investigate the regulation of CES1 by ethanol. Completion of the proposed studies will help elucidate the role of hepatic CES1 in the pathogenesis of ALD and may lead to identification of CES1 as an attractive target for treatment of ALD.